COVID-19 researchGene: IRF2
Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): IRF2 encodes interferon regulatory factor 2, a member of the family of transcription factors that play a role in regulating both the innate and adaptive immune response. IRF2 is an antiviral IFN-stimulated gene (ISG) which negatively regulates IFN signalling. (Lukele et al. 2019 -review). In both cell culture and the knock out Irf2-/- mouse model, Irf2 deficiency leads to an increase in susceptibility to viral infection (Schoggins et al. 2011; Karki et al. 2012; Matsuyama et al. 1993; Grieder et al. 1999). Irf2-/- mice also show increased susceptibility to neurotrophic viruses, including SINV and VSV, when compared to wild type mice. The compromised development and maturation of multiple immune cell types in the Irf2−/− mice which lead to reduced B cells and virus specific IgG levels in the brains of infected mice was linked to the pathogenic phenotype (Melody et al. 2016). These data suggest IRF2 may also play an important role in the development of the immune system.
PMID: 21478870 Schoggins et al. (2011) - The authors over expressed over 380 ISGs to test their ability to inhibit the replication of viruses including hepatitis C virus (HCV), yellow fever virus (YFV), West Nile virus (WNV), chikungunya virus (CHIKV), Venezuelan equine encephalitis virus (VEEV), and human immunodeficiency virus (HIV-1). Each gene was expressed in a lentiviral construct transfected into various cell lines. Cells were challenged with GFP expressing virus and replication was quantified by flow cytometry. IRF2 was shown to be a anti-HCV ISGs.
PMID: 22615998 Karki et al. (2012) - Karki et al. used a library of lentiviruses individually expressing more than 350 ISGs, transduced in HuH-7 cells in the presence of absence of ZAP and identified IRF2 as an enhancer of viral inhibition upon infection with SINV. In confirmatory experiments, when both ZAP and IRF2 were knocked down, viral replication was significantly increased compared to ZAP or IRF2 silencing alone, which supports the results obtained in the ISG overexpression screen and suggests that endogenous ZAP and IRF2 might interact in a synergistic manner (Fig. 5).
PMID: 10208925 Grieder et al. (1999) - Irf2−/− mice show increased susceptibility to virulent Venezuelan equine encephalitis (VEE) virus infection even after vaccination with attenuated VEE, suggesting IRF2 is required to mount a protective immune response (Grieder and Vogel, 1999)
PMID: 22113474 Gao et al. (2012) - The authors found IRF2 variants to be risk alleles for atopic dermatitis and eczema herpeticum. Eight SNPs were found to be significantly associated with reduced IFN-γ production after stimulation with herpes simplex virus. In the cohort, none of the SNPs showed association with HSV positivity.
PMID: 27899441 Melody et al. (2016) - Fig 1. Lrf2 mice show lethality upon peritoneal infection with either SINV or VSV virus (Fig 1) Irf2−/− and WT mice were challenged i.p. with SVN, a neurovirulent but noninvasive strain, which normally replicates only in the periphery without lethality in mice. Approximately 70% of the Irf2−/− mice succumbed to infection with SVN, whereas all of the WT littermate control mice survived (Fig. 1 A), indicating that IRF2 deficiency confers lethal neuroinvasive properties on the normally noninvasive SVN strain. Infection with VSV led to survival of all the WT mice, whereas ∼60% of the Irf2−/− mice suffered from paralysis and succumbed to infection. Staining using Evans blue showed that the integrity of the blood brain barrier is maintained during the infection(fig 2). The survival of lrf-/- mice treated with IFNAR-1 blocking antibody at 2dpi was similar to treatment with a control antibody, suggesting that peripheral elevation of type I IFN signalling is not responsible for the susceptibility (fig 3). Development and maturation of multiple immune cell subsets are compromised in Irf2−/− mice at baseline and upon SVN infection. B cells and virus-specific IgG level are significantly reduced in Irf2 -/- mouse brains, periorbital injection of naïve Bcells from WT mice 1day before infection did not affect lethality in the lrf2-/1 mice.
Created: 28 May 2020, 3:20 p.m. | Last Modified: 28 May 2020, 3:20 p.m.
Panel Version: 0.348
Identified through an OMIM search for potential viral susceptibility genes, and subsequently triaged/reviewed by Illumina curation team.
Created: 28 May 2020, 12:36 p.m. | Last Modified: 28 May 2020, 12:36 p.m.
Panel Version: 0.336
gene: IRF2 was added gene: IRF2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green Mode of inheritance for gene: IRF2 was set to Unknown